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1.
Annu Rev Biochem ; 85: 405-29, 2016 Jun 02.
Artículo en Inglés | MEDLINE | ID: mdl-27088879

RESUMEN

Sirtuins are NAD(+)-dependent enzymes universally present in all organisms, where they play central roles in regulating numerous biological processes. Although early studies showed that sirtuins deacetylated lysines in a reaction that consumes NAD(+), more recent studies have revealed that these enzymes can remove a variety of acyl-lysine modifications. The specificities for varied acyl modifications may thus underlie the distinct roles of the different sirtuins within a given organism. This review summarizes the structure, chemistry, and substrate specificity of sirtuins with a focus on how different sirtuins recognize distinct substrates and thus carry out specific functions.


Asunto(s)
Histonas/química , NAD/química , Procesamiento Proteico-Postraduccional , Sirtuinas/química , Acilación , Expresión Génica , Histonas/genética , Histonas/metabolismo , Humanos , Hidrólisis , Cinética , Lipoilación , Modelos Moleculares , Ácido Mirístico/química , Ácido Mirístico/metabolismo , NAD/metabolismo , Plasmodium falciparum/química , Plasmodium falciparum/enzimología , Estructura Secundaria de Proteína , Sirtuinas/genética , Sirtuinas/metabolismo , Especificidad por Sustrato , Ácido Succínico/química , Ácido Succínico/metabolismo , Thermotoga maritima/química , Thermotoga maritima/enzimología
2.
Chem Rev ; 124(5): 2699-2804, 2024 03 13.
Artículo en Inglés | MEDLINE | ID: mdl-38422393

RESUMEN

The ability to gain spatiotemporal information, and in some cases achieve spatiotemporal control, in the context of drug delivery makes theranostic fluorescent probes an attractive and intensely investigated research topic. This interest is reflected in the steep rise in publications on the topic that have appeared over the past decade. Theranostic fluorescent probes, in their various incarnations, generally comprise a fluorophore linked to a masked drug, in which the drug is released as the result of certain stimuli, with both intrinsic and extrinsic stimuli being reported. This release is then signaled by the emergence of a fluorescent signal. Importantly, the use of appropriate fluorophores has enabled not only this emerging fluorescence as a spatiotemporal marker for drug delivery but also has provided modalities useful in photodynamic, photothermal, and sonodynamic therapeutic applications. In this review we highlight recent work on theranostic fluorescent probes with a particular focus on probes that are activated in tumor microenvironments. We also summarize efforts to develop probes for other applications, such as neurodegenerative diseases and antibacterials. This review celebrates the diversity of designs reported to date, from discrete small-molecule systems to nanomaterials. Our aim is to provide insights into the potential clinical impact of this still-emerging research direction.


Asunto(s)
Colorantes Fluorescentes , Medicina de Precisión , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Fluorescencia , Nanomedicina Teranóstica
3.
Nano Lett ; 24(14): 4082-4090, 2024 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-38526914

RESUMEN

The generally nonpolar SrTiO3 has attracted more attention recently because of its possibly induced novel polar states and related paraelectric-ferroelectric phase transitions. By using controlled pulsed laser deposition, high-quality, ultrathin, and strained SrTiO3 layers were obtained. Here, transmission electron microscopy and theoretical simulations have unveiled highly polar states in SrTiO3 films even down to one unit cell at room temperature, which were stabilized in the PbTiO3/SrTiO3/PbTiO3 sandwich structures by in-plane tensile strain and interfacial coupling, as evidenced by large tetragonality (∼1.05), notable polar ion displacement (0.019 nm), and thus ultrahigh spontaneous polarization (up to ∼50 µC/cm2). These values are nearly comparable to those of the strong ferroelectrics as the PbZrxTi1-xO3 family. Our findings provide an effective and practical approach for integrating large strain states into oxide films and inducing polarization in nonpolar materials, which may broaden the functionality of nonpolar oxides and pave the way for the discovery of new electronic materials.

4.
J Neurochem ; 2024 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-38533619

RESUMEN

Though previous studies revealed the potential associations of elevated levels of plasma fibrinogen with dementia, there is still limited understanding regarding the influence of Alzheimer's disease (AD) biomarkers on these associations. We sought to investigate the interrelationships among fibrinogen, cerebrospinal fluid (CSF) AD biomarkers, and cognition in non-demented adults. We included 1996 non-demented adults from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study and 337 from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The associations of fibrinogen with AD biomarkers and cognition were explored using multiple linear regression models. The mediation analyses with 10 000 bootstrapped iterations were conducted to explore the mediating effects of AD biomarkers on cognition. In addition, interaction analyses and subgroup analyses were conducted to assess the influence of covariates on the relationships between fibrinogen and AD biomarkers. Participants exhibiting low Aß42 were designated as A+, while those demonstrating high phosphorylated tau (P-tau) and total tau (Tau) were labeled as T+ and N+, respectively. Individuals with normal measures of Aß42 and P-tau were categorized as the A-T- group, and those with abnormal levels of both Aß42 and P-tau were grouped under A+T+. Fibrinogen was higher in the A+ subgroup compared to that in the A- subgroup (p = 0.026). Fibrinogen was higher in the A+T+ subgroup compared to that in the A-T- subgroup (p = 0.011). Higher fibrinogen was associated with worse cognition and Aß pathology (all p < 0.05). Additionally, the associations between fibrinogen and cognition were partially mediated by Aß pathology (mediation proportion range 8%-28%). Interaction analyses and subgroup analyses showed that age and ApoE ε4 affect the relationships between fibrinogen and Aß pathology. Fibrinogen was associated with both cognition and Aß pathology. Aß pathology may be a critical mediator for impacts of fibrinogen on cognition.

5.
Small ; : e2312218, 2024 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-38716754

RESUMEN

Room-temperature phosphorescent materials, renowned for their long luminescence lifetimes, have garnered significant attention in the field of optical materials. However, the challenges posed by thermally induced quenching have significantly hindered the advancement of luminescence efficiency and stability. In this study, thermally enhanced phosphorescent carbon nanodots (CND) are developed by incorporating them into fiber matrices. Remarkably, the phosphorescence lifetime of the thermally enhanced CND exhibits a twofold enhancement, increasing from 326 to 753 ms, while the phosphorescence intensity experienced a tenfold enhancement, increasing from 25 to 245 as the temperature increased to 373 K. Rigid fiber matrices can effectively suppress the non-radiative transition rate of triplet excitons, while high temperatures can desorb oxygen adsorbed on the surface of the CND, disrupting the interaction between the CND and oxygen. Consequently, a thermally enhanced phosphorescence is obtained. In addition, benefiting from the thermally enhanced phosphorescence property of CND, a warning indicator with an anti-counterfeiting function for monitoring cold-chain logistics is demonstrated based on CND.

6.
J Transl Med ; 22(1): 598, 2024 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-38937806

RESUMEN

BACKGROUND: Monocyte-derived alveolar macrophages (Mo_AMs) are increasingly recognised as potential pathogenic factors for idiopathic pulmonary fibrosis (IPF). While scRNAseq analysis has proven valuable in the transcriptome profiling of Mo_AMs, the integration analysis of multi-omics may provide additional dimensions of understanding of these cellular populations. METHODS: We performed multi-omics analysis on 116 scRNAseq, 119 bulkseq and five scATACseq lung tissue samples from IPF. We built a large-scale IPF scRNAseq atlas and conducted the Monocle 2/3 as well as the Cellchat to explore the developmental path and intercellular communication on Mo_AMs. We also reported the difference in metabolisms, tissue repair and phagocytosis between Mo_AMs and tissue-resident alveolar macrophages (TRMs). To determine whether Mo_AMs affected pulmonary function, we projected clinical phenotypes (FVC%pred) from the bulkseq dataset onto the scRNAseq atlas. Finally, we used scATATCseq to uncover the upstream regulatory mechanisms and determine key drivers in Mo_AMs. RESULTS: We identified three Mo_AMs clusters and the trajectory analysis further validated the origin of these clusters. Moreover, via the Cellchat analysis, the CXCL12/CXCR4 axis was found to be involved in the molecular basis of reciprocal interactions between Mo_AMs and fibroblasts through the activation of the ERK pathway in Mo_AMs. SPP1_RecMacs (RecMacs, recruited macrophages) were higher in the low-FVC group than in the high-FVC group. Specifically, compared with TRMs, the functions of lipid and energetic metabolism as well as tissue repair were higher in Mo_AMs than TRMs. But, TRMs may have higher level of phagocytosis than TRMs. SPIB (PU.1), JUNB, JUND, BACH2, FOSL2, and SMARCC1 showed stronger association with open chromatin of Mo_AMs than TRMs. Significant upregulated expression and deep chromatin accessibility of APOE were observed in both SPP1_RecMacs and TRMs. CONCLUSION: Through trajectory analysis, it was confirmed that SPP1_RecMacs derived from Monocytes. Besides, Mo_AMs may influence FVC% pred and aggravate pulmonary fibrosis through the communication with fibroblasts. Furthermore, distinctive transcriptional regulators between Mo_AMs and TRMs implied that they may depend on different upstream regulatory mechanisms. Overall, this work provides a global overview of how Mo_AMs govern IPF and also helps determine better approaches and intervention therapies.


Asunto(s)
Fibrosis Pulmonar Idiopática , Macrófagos Alveolares , Monocitos , Humanos , Fibrosis Pulmonar Idiopática/patología , Fibrosis Pulmonar Idiopática/metabolismo , Fibrosis Pulmonar Idiopática/genética , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patología , Monocitos/metabolismo , Masculino , Perfilación de la Expresión Génica , Femenino , Receptores CXCR4/metabolismo , Receptores CXCR4/genética , Persona de Mediana Edad , Fenotipo , Pulmón/patología , Pulmón/metabolismo , Regulación de la Expresión Génica
7.
J Hum Genet ; 69(5): 197-203, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38374166

RESUMEN

CAPZA2 encodes the α2 subunit of CAPZA, which is vital for actin polymerization and depolymerization in humans. However, understanding of diseases associated with CAPZA2 remains limited. To date, only three cases have been documented with neurodevelopmental abnormalities such as delayed motor development, speech delay, intellectual disability, hypotonia, and a history of seizures. In this study, we document a patient who exhibited seizures, mild intellectual disability, and impaired motor development yet did not demonstrate speech delay or hypotonia. The patient also suffered from recurrent instances of respiratory infections, gastrointestinal and allergic diseases. A novel de novo splicing variant c.219+1 G > A was detected in the CAPZA2 gene through whole-exome sequencing. This variant led to exon 4 skipping in mRNA splicing, confirmed by RT-PCR and Sanger sequencing. To our knowledge, this is the third study on human CAPZA2 defects, documenting the fourth unambiguously diagnosed case. Furthermore, this splicing mutation type is reported here for the first time. Our research offers additional support for the existence of a CAPZA2-related non-syndromic neurodevelopmental disorder. Our findings augment our understanding of the phenotypic range associated with CAPZA2 deficiency and enrich the knowledge of the mutational spectrum of the CAPZA2 gene.


Asunto(s)
Proteína CapZ , Discapacidades del Desarrollo , Epilepsia , Heterocigoto , Hipotonía Muscular , Mutación , Preescolar , Femenino , Humanos , Masculino , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/patología , Epilepsia/genética , Secuenciación del Exoma , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Hipotonía Muscular/genética , Hipotonía Muscular/patología , Fenotipo , Empalme del ARN/genética , Proteína CapZ/genética
8.
Opt Express ; 32(1): 785-794, 2024 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-38175098

RESUMEN

Cavity optomechanical (COM) entanglement, playing an essential role in building quantum networks and enhancing quantum sensors, is usually weak and easily destroyed by noises. As feasible and effective ways to overcome this obstacle, optical or mechanical parametric modulations have been used to improve the quality of quantum squeezing or entanglement in various COM systems. However, the possibility of combining these powerful means to enhance COM entanglement has yet to be explored. Here, we fill this gap by studying a COM system containing an intra-cavity optical parametric amplifier (OPA), driven optically and mechanically. By tuning the relative strength and the frequency mismatch of optical and mechanical driving fields, we find that constructive interference can emerge and significantly improve the strength of COM entanglement and its robustness to thermal noises. This work sheds what we believe to be a new light on preparing and protecting quantum states with multi-field driven COM systems for diverse applications.

9.
Opt Express ; 32(12): 22020-22030, 2024 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-38859542

RESUMEN

We propose how to achieve chiral photon blockade by spinning a nonlinear optical resonator. We show that by driving such a device at a fixed direction, completely different quantum effects can emerge for the counter-propagating optical modes, due to the spinning-induced breaking of time-reversal symmetry, which otherwise is unattainable for the same device in the static regime. Also, we find that in comparison with the static case, robust non-classical correlations against random backscattering losses can be achieved for such a quantum chiral system. Our work, extending previous works on the spontaneous breaking of optical chiral symmetry from the classical to purely quantum regimes, can stimulate more efforts towards making and utilizing various chiral quantum effects, including applications for chiral quantum networks or noise-tolerant quantum sensors.

10.
Scand J Immunol ; : e13393, 2024 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-38922971

RESUMEN

It is urgent to explore factors affecting immunotherapy efficacy to benefit non-small cell lung cancer (NSCLC) patient survival. Bioinformatics predicted genes associated with programmed cell death ligand 1 (PD-L1) expression and analysed phospholipase A2 group IID (PLA2G2D) expression in NSCLC. BODIPY 493/503 dye staining and kits detected lipids, triglycerides, and phospholipids in H1299 cells, respectively. Extracellular vesicles (EVs) were extracted for morphology and size assessment using electron microscopy. Western blot assayed CD9, CD63, HSP90, EVs-PD-L1, PD-L1, and PLA2G2D expression. CCK-8, LDH, and ELISA tested proliferation and toxicity of CD8+ T cells, interleukin-2, and interferon-gamma secretion, respectively. PLA2G2D, PD-L1, and Ki67 expression was detected by immunohistochemistry. Immunofluorescence assayed PLA2G2D localisation and CD8+ T cell content. Flow cytometry assessed PD-L1 and CD8 expression. In NSCLC, upregulated EVs-PD-L1 and clinical characteristics showed a strong correlation. H1299 cells with overexpression PD-L1 significantly reduced proliferation, toxicity of CD8+ T cells, and interleukin-2 and interferon-gamma levels. Bioinformatics revealed positive correlations between PLA2G2D and overexpressed PD-L1. PLA2G2D was expressed in macrophages and dendritic cells in NSCLC tissue. Overexpression PLA2G2D (oe-PLA2G2D) increased lipids, triglycerides, and phospholipids contents in H1299 cells. oe-PLA2G2D significantly reduced proliferation, toxicity of CD8+ T cells, and interleukin-2 and interferon-gamma levels. si-PD-L1 restored inhibition of oe-PLA2G2D on CD8+ T cells. oe-PLA2G2D significantly increased mice tumour volume and weight, upregulated expression of blood EVs-PD-L1 and tissue PD-L1, PLA2G2D, Ki67, and decreased CD8+ T cell content. PLA2G2D facilitated immune escape in NSCLC by regulating CD8+ T cell immune function by upregulating EVs-PD-L1.

11.
BMC Cancer ; 24(1): 112, 2024 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-38254060

RESUMEN

BACKGROUND: Since the Z0011 trial, the assessment of axillary lymph node status has been redirected from the previous assessment of the occurrence of lymph node metastasis alone to the assessment of the degree of lymph node loading. Our aim was to apply preoperative breast ultrasound and clinicopathological features to predict the diagnostic value of axillary lymph node load in early invasive breast cancer. METHODS: The 1247 lesions were divided into a high lymph node burden group and a limited lymph node burden group according to axillary lymph node status. Univariate and multifactorial analyses were used to predict the differences in clinicopathological characteristics and breast ultrasound characteristics between the two groups with high and limited lymph node burden. Pathological findings were used as the gold standard. RESULTS: Univariate analysis showed significant differences in ki-67, maximum diameter (MD), lesion distance from the nipple, lesion distance from the skin, MS, and some characteristic ultrasound features (P < 0.05). In multifactorial analysis, the ultrasound features of breast tumors that were associated with a high lymph node burden at the axilla included MD (odds ratio [OR], 1.043; P < 0.001), shape (OR, 2.422; P = 0.0018), hyperechoic halo (OR, 2.546; P < 0.001), shadowing in posterior features (OR, 2.155; P = 0.007), and suspicious lymph nodes on axillary ultrasound (OR, 1.418; P = 0.031). The five risk factors were used to build the predictive model, and it achieved an area under the receiver operating characteristic (ROC) curve (AUC) of 0.702. CONCLUSION: Breast ultrasound features and clinicopathological features are better predictors of high lymph node burden in early invasive breast cancer, and this prediction helps to develop more effective treatment plans.


Asunto(s)
Neoplasias de la Mama , Neoplasias Mamarias Animales , Humanos , Femenino , Animales , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/cirugía , Axila , Ultrasonografía Mamaria , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/cirugía
12.
BMC Cancer ; 24(1): 409, 2024 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-38566057

RESUMEN

BACKGROUND: Accurate evaluation of axillary lymph node metastasis (LNM) in breast cancer is very important. A large number of hyperplastic and dilated lymphangiogenesis cases can usually be found in the pericancerous tissue of breast cancer to promote the occurrence of tumor metastasis.Shear wave elastography (SWE) can be used as an important means for evaluating pericancerous stiffness. We determined the stiffness of the pericancerous by SWE to diagnose LNM and lymphangiogenesis in invasive breast cancer (IBC). METHODS: Patients with clinical T1-T2 stage IBC who received surgical treatment in our hospital from June 2020 to December 2020 were retrospectively enrolled. A total of 299 patients were eventually included in the preliminary study, which included an investigation of clinicopathological features, ultrasonic characteristics, and SWE parameters. Multivariable logistic regression analysis was used to establish diagnostic model and evaluated its diagnostic performance of LNM. The correlation among SWE values, collagen volume fraction (CVF), and microlymphatic density (MLD) in primary breast cancer lesions was analyzed in another 97 patients. RESULTS: The logistic regression model is Logit(P)=-1.878 + 0.992*LVI-2.010*posterior feature enhancement + 1.230*posterior feature shadowing + 0.102*posterior feature combined pattern + 0.009*Emax. The optimum cutoff value of the logistic regression model was 0.365, and the AUC (95% CI) was 0.697 (0.636-0.758); the sensitivity (70.7 vs. 54.3), positive predictive value (PPV) (54.0 vs. 50.8), negative predictive value (NPV) (76.9 vs. 69.7), and accuracy (65.2 vs. 61.9) were all higher than Emax. There was no correlation between the SWE parameters and MLD in primary breast cancer lesions. CONCLUSIONS: The logistic regression model can help us to determine LNM, thus providing more imaging basis for the selection of preoperative treatment. The SWE parameter of the primary breast cancer lesion cannot reflect the peritumoral lymphangiogenesis, and we still need to find a new ultrasonic imaging method.


Asunto(s)
Neoplasias de la Mama , Diagnóstico por Imagen de Elasticidad , Humanos , Femenino , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/cirugía , Linfangiogénesis , Metástasis Linfática/diagnóstico por imagen , Diagnóstico por Imagen de Elasticidad/métodos , Estudios Retrospectivos
13.
Nature ; 558(7711): 569-572, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29950624

RESUMEN

Creating optical components that allow light to propagate in only one direction-that is, that allow non-reciprocal propagation or 'isolation' of light-is important for a range of applications. Non-reciprocal propagation of sound can be achieved simply by using mechanical components that spin1,2. Spinning also affects de Broglie waves 3 , so a similar idea could be applied in optics. However, the extreme rotation rates that would be required, owing to light travelling much faster than sound, lead to unwanted wobbling. This wobbling makes it difficult to maintain the separation between the spinning devices and the couplers to within tolerance ranges of several nanometres, which is essential for critical coupling4,5. Consequently, previous applications of optical6-17 and optomechanical10,17-20 isolation have used alternative methods. In hard-drive technology, the magnetic read heads of a hard-disk drive fly aerodynamically above the rapidly rotating disk with nanometre precision, separated by a thin film of air with near-zero drag that acts as a lubrication layer 21 . Inspired by this, here we report the fabrication of photonic couplers (tapered fibres that couple light into the resonators) that similarly fly above spherical resonators with a separation of only a few nanometres. The resonators spin fast enough to split their counter-circulating optical modes, making the fibre coupler transparent from one side while simultaneously opaque from the other-that is, generating irreversible transmission. Our setup provides 99.6 per cent isolation of light in standard telecommunication fibres, of the type used for fibre-based quantum interconnects 22 . Unlike flat geometries, such as between a magnetic head and spinning disk, the saddle-like, convex geometry of the fibre and sphere in our setup makes it relatively easy to bring the two closer together, which could enable surface-science studies at nanometre-scale separations.

14.
Acta Pharmacol Sin ; 45(7): 1477-1491, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38538716

RESUMEN

Refractory wounds are a severe complication of diabetes mellitus that often leads to amputation because of the lack of effective treatments and therapeutic targets. The pathogenesis of refractory wounds is complex, involving many types of cells. Rho-associated protein kinase-1 (ROCK1) phosphorylates a series of substrates that trigger downstream signaling pathways, affecting multiple cellular processes, including cell migration, communication, and proliferation. The present study investigated the role of ROCK1 in diabetic wound healing and molecular mechanisms. Our results showed that ROCK1 expression significantly increased in wound granulation tissues in diabetic patients, streptozotocin (STZ)-induced diabetic mice, and db/db diabetic mice. Wound healing and blood perfusion were dose-dependently improved by the ROCK1 inhibitor fasudil in diabetic mice. In endothelial cells, fasudil and ROCK1 siRNA significantly elevated the phosphorylation of adenosine monophosphate-activated protein kinase at Thr172 (pThr172-AMPKα), the activity of endothelial nitric oxide synthase (eNOS), and suppressed the levels of mitochondrial reactive oxygen species (mtROS) and nitrotyrosine formation. Experiments using integrated bioinformatics analysis and coimmunoprecipitation established that ROCK1 inhibited pThr172-AMPKα by binding to receptor-interacting serine/threonine kinase 4 (RIPK4). These results suggest that fasudil accelerated wound repair and improved angiogenesis at least partially through the ROCK1/RIPK4/AMPK pathway. Fasudil may be a potential treatment for refractory wounds in diabetic patients.


Asunto(s)
1-(5-Isoquinolinesulfonil)-2-Metilpiperazina , Diabetes Mellitus Experimental , Transducción de Señal , Cicatrización de Heridas , Quinasas Asociadas a rho , Animales , Quinasas Asociadas a rho/metabolismo , Quinasas Asociadas a rho/antagonistas & inhibidores , Cicatrización de Heridas/efectos de los fármacos , Humanos , Diabetes Mellitus Experimental/metabolismo , Masculino , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/farmacología , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/uso terapéutico , Ratones , Transducción de Señal/efectos de los fármacos , Ratones Endogámicos C57BL , Proteínas Quinasas Activadas por AMP/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Células Endoteliales de la Vena Umbilical Humana , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III/metabolismo , Femenino
15.
Proc Natl Acad Sci U S A ; 118(41)2021 10 12.
Artículo en Inglés | MEDLINE | ID: mdl-34607960

RESUMEN

Human genetic studies have pointed to a prominent role for innate immunity and lipid pathways in immunological and neurodegenerative disorders. Our understanding of the composition and function of immunomodulatory lipid networks in innate immune cells, however, remains incomplete. Here, we show that phospholipase Cγ2 (PLCγ2 or PLCG2)-mutations in which are associated with autoinflammatory disorders and Alzheimer's disease-serves as a principal source of diacylglycerol (DAG) pools that are converted into a cascade of bioactive endocannabinoid and eicosanoid lipids by DAG lipase (DAGL) and monoacylglycerol lipase (MGLL) enzymes in innate immune cells. We show that this lipid network is tonically stimulated by disease-relevant human mutations in PLCγ2, as well as Fc receptor activation in primary human and mouse macrophages. Genetic disruption of PLCγ2 in mouse microglia suppressed DAGL/MGLL-mediated endocannabinoid-eicosanoid cross-talk and also caused widespread transcriptional and proteomic changes, including the reorganization of immune-relevant lipid pathways reflected in reductions in DAGLB and elevations in PLA2G4A. Despite these changes, Plcg2-/- mice showed generally normal proinflammatory cytokine and chemokine responses to lipopolysaccharide treatment, instead displaying a more restricted deficit in microglial activation that included impairments in prostaglandin production and CD68 expression. Our findings enhance the understanding of PLCγ2 function in innate immune cells, delineating a role in cross-talk with endocannabinoid/eicosanoid pathways and modulation of subsets of cellular responses to inflammatory stimuli.


Asunto(s)
Eicosanoides/metabolismo , Endocannabinoides/metabolismo , Inmunidad Innata/inmunología , Macrófagos/inmunología , Fosfolipasa C gamma/metabolismo , Animales , Antígenos CD/biosíntesis , Antígenos de Diferenciación Mielomonocítica/biosíntesis , Células COS , Línea Celular , Chlorocebus aethiops , Citocinas/inmunología , Diglicéridos/metabolismo , Fosfolipasas A2 Grupo IV/metabolismo , Células HEK293 , Humanos , Inflamación/inmunología , Lipopolisacáridos/inmunología , Lipoproteína Lipasa/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/inmunología , Monoacilglicerol Lipasas/metabolismo , Fosfolipasa C gamma/genética , Prostaglandinas/biosíntesis , Receptores Fc/inmunología , Transducción de Señal/inmunología
16.
Proc Natl Acad Sci U S A ; 118(14)2021 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-33785600

RESUMEN

The contraction of heart cells is controlled by the intermolecular signaling between L-type Ca2+ channels (LCCs) and ryanodine receptors (RyRs), and the nanodistance between them depends on the interaction between junctophilin-2 (JPH2) in the sarcoplasmic reticulum (SR) and caveolin-3 (CAV3) in the transversal tubule (TT). In heart failure, decreased expression of JPH2 compromises LCC-RyR communication leading to deficient blood-pumping power. In the present study, we found that JPH2 and CAV3 transcription was concurrently regulated by serum response factor (SRF) and myocardin. In cardiomyocytes from torpid ground squirrels, compared with those from euthermic counterparts, myocardin expression was up-regulated, which boosted both JPH2 and CAV3 expression. Transmission electron microscopic imaging showed that the physical coupling between TTs and SRs was tightened during hibernation and after myocardin overexpression. Confocal Ca2+ imaging under the whole-cell patch clamp condition revealed that these changes enhanced the efficiency of LCC-RyR intermolecular signaling and fully compensated the adaptive down-regulation of LCCs, maintaining the power of heart contraction while avoiding the risk of calcium overload during hibernation. Our finding not only revealed an essential molecular mechanism underlying the survival of hibernating mammals, but also demonstrated a "reverse model of heart failure" at the molecular level, suggesting a strategy for treating heart diseases.


Asunto(s)
Señalización del Calcio , Hibernación , Miocitos Cardíacos/metabolismo , Animales , Caveolinas/genética , Caveolinas/metabolismo , Células Cultivadas , Acoplamiento Excitación-Contracción , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas Nucleares/sangre , Proteínas Nucleares/metabolismo , Sciuridae , Transactivadores/sangre , Transactivadores/metabolismo
17.
BMC Med Educ ; 24(1): 37, 2024 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-38191374

RESUMEN

BACKGROUND: Reports of emotional, existential and moral distress amongst medical students witnessing death and suffering of patients during their clinical postings have raised awareness on the need for better psycho-emotional support during medical school. Furthermore, the stress experienced by medical students stemming from the rigours of their academic curriculum underlines the need for greater awareness on mental health issues and better self-care practices across medical training. With such programmes lacking in most medical schools, we propose a systematic scoping review (SSR) to map and address our research question, "what is known about self-care education interventions amongst medical students?". METHODS: We adopted the Systematic Evidence-Based Approach to guide a systematic scoping review (SSR in SEBA) of relevant articles published between 1st January 2000 and 30th June 2023 in PubMed, Embase, PsycINFO, ERIC, Google Scholar, and Scopus databases. The included articles were independently and concurrently thematically and content analysed, with complementary categories and themes combined using the Jigsaw Approach. The domains created from the Funnelling Process framed the discussion. RESULTS: A total of 6128 abstracts were identified, 429 full-text articles evaluated, and 147 articles included. The 6 domains identified were definition, topics, pedagogy, influences, outcomes and assessment. Most interventions were promising, though peer-led mindfulness-based interventions showed most promise in enhancing engagement, positively impacting personal wellbeing, and improving patient care. Overall, however, self-care education was poorly recognized, adopted and integrated into curricula. CONCLUSION: Greater dedicated time and conducive practice environments within medical school curricula is required to enhance medical student wellbeing. Host organizations must ensure faculty are appropriately selected to instil the importance of self-care, be trained to assess and personalize self-care interventions and provide longitudinal assessment and support. Further study into assessing self-care capabilities is required.


Asunto(s)
Autocuidado , Estudiantes de Medicina , Humanos , Ansiedad , Curriculum , Bases de Datos Factuales , Estudiantes de Medicina/psicología
18.
Nano Lett ; 23(4): 1522-1529, 2023 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-36722976

RESUMEN

Antiferroelectrics characterized by voltage-driven reversible transitions between antiparallel and parallel polarity are promising for cutting-edge electronic and electrical power applications. Wide-ranging explorations revealing the macroscopic performances and microstructural characteristics of typical antiferroelectric systems have been conducted. However, the underlying mechanism has not yet been fully unraveled, which depends largely on the atomistic processes. Herein, based on atomic-resolution transmission electron microscopy, the deterministic phase transition pathway along with the underlying lattice-by-lattice details in lead zirconate thin films was elucidated. Specifically, we identified a new type of ferrielectric-like dipole configuration with both angular and amplitude modulations, which plays the role of a precursor for a subsequent antiferroelectric to ferroelectric transformation. With the participation of the ferrielectric-like phase, the phase transition pathways driven by the phase boundary have been revealed. We provide new insights into the consecutive phase transformation in low-dimensional lead zirconate, which thus would promote potential antiferroelectric-based multifunctional devices.

19.
J Prosthet Dent ; 2024 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-39013680

RESUMEN

STATEMENT OF PROBLEM: While repurposing waste materials into zirconia blocks presents a promising avenue, uncertainty remains regarding whether the bonding properties of recycled zirconia align with those of commercially available zirconia. PURPOSE: The purpose of this in vitro study was to evaluate the bonding affinity and durability of composite resin to recycled zirconia. MATERIAL AND METHODS: A series of processing steps were performed with recycled zirconia residuals (Lava Plus; 3M Oral Care), including pulverization, sieving, heating, compaction, isostatic pressing, and presintering. The presintered blocks of recycled zirconia (Group R) and commercially available zirconia (Group C) were sectioned and sintered to create test specimens (10×10×1.5 mm). After polishing and airborne-particle abrasion, specimens within each group were bonded to composite resin cylinders using a resin cement (Multilink Speed; Ivoclar AG). The specimens were then divided into 3 subgroups for shear bond strength (SBS) testing: no further treatment, 10 000 thermocycles, and 30 000 thermocycles (n=10). X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive X-ray spectrometry (EDS), surface roughness, and contact angle were used to analyze the surface physicochemical differences between Groups C and R. Data were analyzed with 2-way ANOVA followed by the Tukey post hoc test for SBS values, Pearson chi-squared test for failure modes, and independent t test for grain size, surface roughness, and wettability (α=.05). RESULTS: No significant difference was found in the SBS values between Group R and Group C (P=.403), while thermocycling significantly affected the SBS values (P<.05). Group R showed significantly greater Ra, Rz, and Rq values (P<.05) than did Group C. SEM analysis revealed that Group R exhibited more prominent grooves than Group C, while the XRD and EDS patterns exhibited similarities in both the crystalline phase and elemental composition. No significant difference was observed in the water contact angle between the 2 groups (P=.196). CONCLUSIONS: The bonding protocol established for commercially available zirconia was comparable with that of recycled zirconia, but both decreased after thermocycling. The recycling process did not affect the crystalline phase or elemental composition of the zirconia, but it induced alterations in the surface roughness.

20.
Sheng Li Xue Bao ; 76(3): 394-406, 2024 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-38939934

RESUMEN

Spinal cord injury (SCI) is a serious central nervous system disease with high disability and mortality rates and complex pathophysiologic mechanisms. MicroRNA (miRNA), as a kind of non-coding RNA, plays an important role in SCI. miRNA is involved in the regulation of inflammatory response, oxidative stress, axonal regeneration, and apoptosis after SCI, and interacts with long non-coding RNA (lncRNA) and circular RNA (circRNA) to regulate the pathophysiological process of SCI. This paper summarizes the changes in miRNA expression after SCI, and reviews the targeting mechanism of miRNA in SCI and the current research status of miRNA-targeted drugs to provide new targets and new horizons for basic and clinical research on SCI.


Asunto(s)
MicroARNs , Traumatismos de la Médula Espinal , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/fisiopatología , MicroARNs/genética , MicroARNs/metabolismo , MicroARNs/fisiología , Humanos , Animales , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN Largo no Codificante/fisiología , ARN Circular/genética , ARN Circular/fisiología , ARN Circular/metabolismo , Estrés Oxidativo , Apoptosis/genética
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